The G-protein-coupled receptors (GPCR) form an important class of peptide-binding receptors. The various members of the GPCR family mediate a wide variety of intercellular signals.
Members of the GPCR family have seven helical domains which span the cell membrane and are linked by three extracellular loops and three intracellular loops. The receptors also posses an extracellular amino terminal tail and an intracellular carboxy terminal tail. The intracellular loops interact with a G-protein that can switch from a GDP-binding form to a GTP-binding form.
The binding of an appropriate ligand to a GPCR initiates the conversion of the coupled G-protein from its GDP-binding form to its GTP-binding form. This conversion, in turn, initiates a signal transduction cascade that generates a biological response. Depending on the nature of the GPCR, signal transduction activity can be measured by measuring the intracellular Ca.sup.2+ level, phospholipase C activation, the inositol triphosphate (IP.sub.3) level, the diacylglycerol level, or the adenosine cyclic 3', 5'-monophosphate (AMP) level.
Marchese et al. (Genomics 29:335, 1995) describes the cloning and chromosomal mapping of GPR10, a human GPCR. Marchese et al. analyzed GPR10 expression in the brain and reported that no human GPR10 expression was observed in hypothalamus, putamen, pons, hippocampus, frontal cortex, thalamus, and cerebellum.
Welch et al. (Biochem. Biophys Res. Comm. 209:606, 1995) describes the cloning of UHR-1, a rat GPCR, from the hypothalamic suprachiasmatic nucleic, the circadian pacemaker of the human brain. According to Welch et al., UHR-1 has sequence similarity at the amino acid level to the receptors for the tachykinins, substance P, and substance K; the somatostatin receptors SSTR5 and SSTR3; the neuropepticle Yl receptor; the delta, kappa, and mu opioid receptors, and the gastrin-CCK-B receptor. According to Welch et al., rat UHR-1 is expressed in rat pituitary, cerebellum, hypothalamus, pons, and hippocampus. No expression is present in rat neonatal brain, adult rat liver, lung, pancreas, kidney, spleen, small intestine, adrenal gland, testes, thymus, aorta, heart, skeletal muscle, or diaphragm.
Duhl (PCT Publication No. WO 97/08317) describes a protein referred to as "human hypothalamic receptor" or "hHR". According to Duhl, hHR is a seven-transmembrane receptor. Duhl suggests that hHR can be used to identify agonists and antagonists of hHR activity.
Hinuma et al. (EP 0 845 529 A2) discloses two forms of a G-protein coupled receptor protein. Hinuma et al. report that one of the two forms of the disclosed G protein coupled receptor is expressed in the brain.
Hinuma et al. (Nature 393:272, 1998) describes "prolactin-releasing peptide" (PrRP) a peptide which binds to hGR3, a receptor that is expressed in human pituitary and is, according to Hinuma et al., nearly identical to both GPR10 and the human homologue of rat UHR-1. Hinuma et al. report that PrRP stimulates release of prolactin from anterior pituitary cells of lactating rats in vitro. Hinuma et al. also report that expression of PrRP and its receptor appear to fluctuate in the medulla oblongata and pituitary during pregnancy and lactation, respectively, in rats. Based on these results, Hinuma et al. suggest that the levels of PrRP and its receptor are closely related to the regulation of reproductive processes.